Recent experimental data revealed that in addition to its well-known role in mineral and skeletal metabolism, vitamin D is involved in the regulation of growth, differentiation and function of a wide range of normal and malignant cells. Vitamin D-specific receptors are present in normal mammalian ovaries, in human ovarian tissues and in the ovarian carcinoma cell lines. Administration of active vitamin D compounds had been associated with a considerable prodifferentiation and antiproliferative changes in ovarian cells, induction of apoptosis, modulation of growth factor signaling and inhibition of invasion and metastasis. The current application proposes to test the hypothesis that vitamin D may be essential in supporting the differentiated/antiproliferative phenotype of ovarian cells, whereas hypovitaminosis D (due to low serum levels of active vitamin D compounds and/or due to vitamin D receptor gene polymorphisms) is associated with an increased risk of ovarian cancer. The primary specific aim of this application is to conduct the first analytical study to examine serum levels of 25-hydroxyvitamin-D3, an active form of vitamin D, as biomarker of ovarian cancer risk. The secondary specific aim is to assess the possible role of functional vitamin D receptor gene polymorphisms (Taql, BsmI, ApaI, poly-A microsatellite) in ovarian cancer. The proposed nested case-control study is based on two existing prospective cohorts: the New York University Women's Health Study (NYUWHS) and the Northern Sweden Health and Disease Study (NSHDS). Besides the valuable source of biological specimens, which include serum and DNA samples, NYUWHS and NSHDS provide the established mechanisms of follow-up. At least 136 cases of ovarian cancer are available for the study (80 cases from the NYUWHS and 56 cases from the NSHDS), as well as 272 individually-matched controls. Demonstration of the role of vitamin D as a potential biomarker of ovarian cancer risk would have a direct clinical implications: 1) serum levels of vitamin D and/or vitamin D receptor polymorphisms could be used to identify women at increased risk of ovarian cancer, which is currently characterized by lack of reliable biomarkers for screening and early detection; 2) an intervention with vitamin D analogues with limited calcium mobilizing activity could be a potentially new therapeutic approach for primary chemoprevention of ovarian cancer.